Stereospecific total steroidal synthesis via substituted C/D-trans indanones

ABSTRACT

Total synthesis of known progestationally active steroidal materials. The steroids can be synthesized depending on the particular starting reactants selected by employing as intermediates bicyclic compounds of the formula ##SPC1## 
     Wherein m is an integer having a value of 1 or 2; R 4  is hydrogen or lower alkyl; Z is lower alkylenedioxymethylene CH(OR 2 ) and carbonyl; R 8  when taken alone is hydrogen; R 9  when taken alone is lower alkoxycarbonyl, aryloxy-carbonyl, lower cycloalkyloxycarbonyl, carbonyl-halide, hydrogen, carboxy, formyl and methylene-X, where X is a leaving group and when taken together are methylene; with the proviso that when Z is carbonyl R 8  when taken alone is hydrogen; R 9  when taken alone is carbonyl halide, hydrogen, carboxy, formyl and methylene-X where X is a leaving group and when taken together are methylene and R 2  is hydrogen, lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl, tetrahydropyranyl, lower alkanoyl, benzoyl, nitrobenzoyl, carboxy-lower alkanoyl, carboxybenzoyl, trifluoroacetyl and camphorsulfonyl 
     And reacting them in the case where R 8  and R 9  taken together are methylene or R 8  is hydrogen and R 9  is methylene-X with β-keto esters and other analogs of the formula ##EQU1## wherein R.sub. 6 is selected from the group CONSISTING OF ##EQU2##  and LOWER ALKYL; R 7  is lower alkyl; R 15  is selected from the group consisting of oxo, lower alkylene-dioxy or (hydrogen and lower alkoxy); B is selected from the group consisting of lower alkoxy-carbonyl-methylene, lower-aryloxy-carbonyl-methylene, cyanomethylene, lower alkyl sulfinyl-methylene, lower alkyl sulfonyl-methylene, and R 25  and R 26  are independently selected from the group consisting of hydrogen, hydroxyl and lower alkyl.

This is a division of application Ser. No. 765,023 filed Oct. 4, 1968now U.S. Pat. No. 3,897,460.

BACKGROUND OF THE INVENTION

In recent years, much effort has been devoted to the total synthesis ofsteroids. The present invention relates to certain polycyclic compoundsand processes for their synthesis. The novel intermediates and processesof this invention provide a new synthetic route for the preparation ofpharmaceutically valuable steroids.

SUMMARY OF THE INVENTION

In one aspect, this invention relates to a process for preparingintemediates useful in the preparation of tricyclic compounds of theformula ##SPC2##

Wherein R₁ is hydrogen or lower alkyl; R₄ is hydrogen or lower alkyl; Zis defined hereinafter; m is an integer having the value of 1 or 2.

Another aspect of this invention relates to a process for preparingintermediates which enable the direct preparation of steroids of theformulae ##SPC3##

Wherein R₁, R₄ and m are as defined above; Z is defined hereinafter; R₁₁is hydrogen or lower alkyl and R₂₅ and R₂₆ are independently selectedfrom the group consisting of a lower alkyl, hydrogen and hydroxyl.

In accordance with this invention, it has been discovered that compoundsof the formulae I, II and III above, can be synthesized depending on theparticular starting reactants selected by employing as intermediatesbicyclic compounds of the formula ##SPC4##

wherein m is an integer having a value of 1 or 2; R₄ is hydrogen orlower alkyl; Z is lower alkylenedioxy methylene, CH(OR₂) and carbonyl;R₈ when taken alone is hydrogen; R₉ when taken alone is loweralkoxycarbonyl, aryloxy-carbonyl, lower cycloalkyloxycarbonyl,carbonyl-halide, hydrogen, carboxy, formyl and methylene-X, where X is aleaving group and when taken together are methylene; with the provisothat when Z is carbonyl, R₈ when taken alone is hydrogen; R₉ when takenalone is carbonyl halide, hydrogen, carboxy, formyl and methylene-Xwhere X is a leaving group and when taken together are methylene and R₂is hydrogen, lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl,tetrahydropyranyl, lower alkanoyl, benzoyl, nitrobenzoyl, carboxy-loweralkanoyl, carboxybenzoyl, trifluoroacety and camphorsulfonyl

and reacting them in the case where R₈ and R₉ taken together aremethylene or R₈ is hydrogen and R₉ is methylene-X with β-keto esters andother analogs of the formula ##EQU3## wherein R₆ is selected from thegroup consisting of ##EQU4## and lower alkyl; R₇ is lower alkyl; R₁₅ isselected from the group consisting of oxo, lower alkylenedioxy or(hydrogen and lower alkoxy); B is selected from the group consisting oflower alkoxy-carbonyl-methylene, lower-aryloxy-carbonyl-methylene,cyanomethylene, lower alkyl sulfinyl-methylene, loweralkylsulfonyl-methylene, and R₂₅ and R₂₆ are independently selected fromthe group consisting of hydrogen, hydroxyl and lower alkyl.

In still another aspect, this invention relates to the preparation ofthe compounds of formula III above wherein R₁₁ is hydrogen, by reactingthe compounds of formulae IV-a and IV-c with a vinylogouscyclic-beta-keto compound of the formula: ##SPC5##

wherein B' is selected from the group consisting of lower alkoxycarbonyl-methylene, lower aryloxy carbonyl-methylene, lower alkylsulfinyl-methylene and lower alkyl sulfonyl-methylene.

Structure III can also be obtained starting with a compound of theformula V, in which R₁₅ has been chosen to be oxo by reaction withcompounds of the formulae IV-a and IV-c.

A further aspect of this invention relates to novel intermediates of theformula IV. Subgeneric to the bicyclic compound of formula IV above arecompounds of the formulae: ##SPC6##

wherein R₄, Z, m and X are as defined aforesaid; Y is selected from thegroup consisting of fluorine, chlorine, bromine and iodine and R's isselected from the group consisting of lower alkyl, lower cycloalkyl andaryl.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, this invention is concerned with novel indanones of theformulae IV, IV-a, IV-b, IV-c, IV-d, IV-e and IV-f which are useful aschemical intermediates as described herein. Also, certain of the ketocompounds of formula V are novel and are also considered within thescope of this invention. For purposes of convenience, the rings informulae I and IV have been numbered. Throughout this specification, inthe formulae of compounds containing asymmetric centers or in thedesignation of such compounds by chemical nomenclature, the desiredenantiomeric form is shown or designated. However, unless explicitlyindicated otherwise, such illustration and designation should be takenas comprehending the enantiomer shown or designated, as well as itsoptical antipode or their corresponding racemate. In the formulaepresented herein, the various substituents on cyclic compounds arejoined to the cyclic nucleus by one of two notations, a solid line (--)indicating a substituent which is in the β-orientation (i.e., above theplane of the paper), or a dotted line (- - - - -) indicating asubstituent which is in the α-orientation (below the plane of thepaper).

As used herein, the term "lower alkyl" comprehends both side andbranched chain hydrocarbon moieties such as methyl, ethyl, isopropyl,n-propyl, t-butyl and the like, having 1 to 7 carbon atoms in the chain.The preferred compounds are those derivatives wherein R₄ methyl, ethyland propyl which can be converted into steroids which exhibitexceptionally active pharmacological properties as hereinafterdescribed. The formative "lower-alkyl" when used in expressions such aslower alkoxy-lower alkyl have the same significance. Thus, exemplary ofthe expression lower alkoxy-lower alkyl is α-ethoxy-ethyl and3-propoxy-propyl. Exemplary of lower alkanoyl are acetyl and propionylor other residues derived from lower alkane carboxylic acids of 1 to 6carbon atoms; lower alkylenedioxy is understood to mean alkylene of 1 to6 carbon atoms exemplary of which is ethylenedioxy. The term"nitrobenzoyl" as used herein comprehends benzo moieties containing oneor more aromatic nitrile substituents, for example, nitrobenzoylmoieties such as 4-nitrobenzoyl and di-nitrobenzoyl moieties such as3,5-dinitrobenzoyl. The expression carboxy-lower alkanoyl comprehendsdi-basic aliphatic acids of 1 to 7 carbon atoms absent one OH moiety.Similarly, the expression "carboxy-benzoyl" denotes, for example,phthalic acids absent one OH moiety. The expression "halide" or"halogen" comprehends chlorine, fluorine, bromine and iodine. Theexpression "lower alkoxy" as utilized herein designates a lower alkylether group such as methoxy, ethoxy and the like, wherein the alkylgroup is as defined above. The term "lower alkoxy carbonyl methylene"includes for example, ethoxy carbonyl-methylene. The term "lower aryloxycarbonyl methylene" includes for example, phenyloxy carbonyl methylene.The term "aryl" comprehends phenyl or phenyl having one or moresubstituents selected from the group consisting of lower alkyl, loweralkoxy, nitro, amine and halogen. The expression "lower alkylaryl"comprehends, for example, tolyl and ethylphenyl. The term cycloalkylincludes rings containing from 1 to 6 atoms, for example, cycloalkyl andcyclopentyl. Especially preferred compounds of formula IV are thosewherein Z is lower alkoxy methylene, especially t-butoxy methylenealthough the other derivatives defined hereinabove such as,tetrahydropyranyloxy methylene can be suitably employed in accordancewith the process of this invention.

The following schematic flow sheet entitled "Reaction Scheme A",exemplifies the process routes employed in accordance with the teachingsof this invention for preparation via process routes (1), (2), (3), (4),(5), (6), (7), (8), (9) and (10), the key intermediates of the formulaeIV-c and IV-a, each of which can independently be reacted with theβ-keto esters and other analogs thereof of formula V to yield theend-products of formulae I, II and III as hereinafter detailed.

Thus, in one aspect of the process of this invention, comprisespreparing compounds of the formula IV-a by the general reaction steps(1), (2) and (4) of Reaction Scheme A to which the numerals and lettersin parenthesis are referenced in the following descriptions.

Many of the indanone starting reactants of formula VII wherein Z iscarbonyl are known. They may be conveniently synthesized by methodsknown in the art, for example, by the Michael Addition ofmethyl-vinyl-ketone to 2-lower alkyl-cyclopentane-1,3-dione. Thecyclization can be effected using pyrrolidine in a benzene solvent underreflux reaction conditions (cf., U.S. Pat. No. 3,321,488). If desired,other derivatives of formula VII may be prepared. For example, in orderto prepare the derivatives wherein Z is hydroxy, the corresponding oxogroup can be selectively reduced with lithium aluminum tri-(loweralkoxy)-hydride or sodium borohydride at low temperatures. Derivativeswherein Z is lower alkoxy methylene, for example, tertiarybutoxymethylene, can be obtained from the corresponding hydroxy derivative byreaction under acid conditions with isobutylene by means known in theart. 1-Carboxy-lower alkanoyl derivatives of formula VII can beconveniently obtained by reacting dibasic lower alkanoic acids such as,succinic acid and phthalic acid and the like, with correspondingcompounds containing the hydroxy-methylene moiety. Other derivatives inaccordance with the definition of Z can be obtained by methods known tothose skilled in the art. ##SPC7##

wherein R₄, Z, m, R'₃, X and Y are as defined aforesaid.

The bicyclic ketone of formula VII can be converted to acid compounds offormula VIII by reaction in accordance with Step (1) of Reaction SchemeA with a base sufficiently strong to afford the corresponding anion ofthe bicyclic compound via conjugate enolate formation. Exemplary of thesuitable bases for this reaction are alkali metal amides such as sodiumamide and the like; alkali metal alkoxides such as lithium methoxide andthe like and alkali metal hydrides such as sodium hydride. Generally, itis preferred to conduct this reaction at room temperature althoughtemperatures from about -40° C. to the boiling point of the reactionmixture can be utilized. The reaction is conveniently carried out inliquid ammonia or in the presence of an organic solvent inert to thereactants such as dimethylsulfoxide, dimethylformamide; hydrocarbons,e.g., benzene and toluene; and ethers, e.g., diethylether andtetrahydrofuran. A preferred solvent for this reaction isdimethylsulfoxide. This intermediate enolate bicyclic reaction productcan be isolated by conventional techniques such as, for example, byremoval of the solvent using vacuum distillation.

The anion which is thus obtained as a residue can be carboxylated byreaction with excess carbon dioxide to afford the 4-indane carbocyclicacid of the formula VIII. The carboxylation can be suitably effected byemploying solid carbon dioxide in the form of dry ice or passing gaseouscarbon dioxide into the reaction medium. Exemplary of the desirablesolvents for this reaction are any of the aforementioned listed solventswhich can be employed to prepare the anion with the exception of liquidammonia, which in basic and dimethylsulfoxide, which tends to promotedecarboxylation. In cases wherein liquid ammonia or dimethylsulfoxide isemployed to prepare the anion, an inert solvent should be substitutedwhen conducting the carbonation reaction. Suitable reaction temperaturesare in the range of -60° and about 40° C. A preferred operatingtemperature range is 15°-25° C. Separation of the desired reactionproduct from the reaction medium can be effected by extraction. Theextraction is suitably conducted in a hydrocarbon solvent in thepresence of a dilute base such as sodium hydroxide or lithium carbonateto form the corresponding water soluble salt of the acid. Baseextraction is employed so as to remove the desired product from thestarting material. The aqueous layer is separated and carefullyacidified to a pH of between 2.5 and 4.5 with dilute mineral acid andthe desired product is then obtained by conventional techniques.Although the reaction can be suitably conducted at atmospheric pressure,increased yields can be obtained by conducting the reaction under higherpressures, e.g., in the range of 450 to 550 psi. Carboxylation takesplace only at C-4 position on the indane nucleus in agreement with thepreference for heteroannular conjugate anion formation with compoundVII.

Inasmuch as the ultimate goal of this invention is to produce a compoundof the formula I containing a 9bα-configuration, it is clear that thehydrogenation of the compound of formula VIII in accordance with Step(2) of Reaction Scheme A must predominantly proceed so as to yield atrans-hydrogenation product with respect to the two rings of the5-indanone or the corresponding 2-naphthalenone compounds. A feature ofthis invention is that the desired hydrogenation to yield a transfusedbicyclic structure can be effected in extremely high yields. Thehydrogenation is conducted in the presence of a catalyst preferably anoble metal catalyst, such as palladium, rhodium, irridium, platinum andthe like. Especially preferred is the palladium catalyst. The noblemetal catalyst can be utilized with or without a carrier and if acarrier is used, conventional carriers are suitable. It is preferred touse palladium on barium or calcium sulfate. Especially preferred is 10percent Pd/BaSO₄. The ratio of catalyst to substrate is not critical andcan be varied. However, it has been found advantageous to use a weightratio of catalyst to substrate from about 1:1 to about 1:10. Especiallypreferred is a ratio of 1:3. The hydrogenation is suitably effected inthe presence of an inert organic solvent for the particular compound offormula VII being hydrogenated, for example, a lower alkanol, such asmethanol, isopropanol or octanol; ketones for example, lower alkylketones such as acetone or methylethyl ketone; lower alkyl esters oflower alkanoic acids such as ethyl acetate; lower alkyl ethers such asdiethyl ether to tetrahydrofuran; aromatic hydrocarbons such as tolueneor benzene and the like. It is especially preferred to conduct thehydrogenation using a lower alkanol as the solvent and it is preferablyconducted under non-acidic conditions. Suitably, the hydrogenation isconducted under neutral conditions. It can be conducted at atmosphericpressure or below or above atmospheric pressure, for example, atpressures of as high as about 50 atmosphere. Also, the hydrogenation canbe conducted at room temperature or temperatures above or below roomtemperature. As a matter of convenience, it is preferred to conduct thehydrogenation at room temperature. The hydrogenation is effected byutilizing conventional techniques, for example, the hydrogenation shouldbe stopped after the uptake of the equivalent of hydrogen or if theabsorption of hydrogen ceases before the uptake of an equivalent ofhydrogen, it is advantageous to then add more catalyst and furtherhydrogenate. It will be appreciated that another significant aspect ofthis hydrogenation step lies in that the hydrogenation of the compoundof formula VIII to afford the compound of formula IV-f proceeds withoutsubstantial decarboxylation of the substituted indane of formula VIII.Depending on the hydrogenation conditions used, the group represented byZ in formula VIII can be modified during the hydrogenation. For example,under the above-described hydrogenation conditions, when Z is OR₂ and R₂is a group such as alkoxy-lower alkyl or tetrahydropyranyl, such groupcan be split off during the hydrogenation procedure. A preferred groupfor R₂ in which to conduct the hydrogenation and many of the subsequentother reactions is alkyl, especially, t-butyl.

The thus obtained saturated compound of formula IV-f can be converted tothe 4-methylene-trans-fused compounds of formula IV-a by employing amodified Mannich-type reaction in accordance with Step (4) of ReactionScheme A. The conversion can be effected using formaldehyde in thepresence of a primary or secondary amine salts. Suitable salts which maybe employed are those derived from strong mineral or organic acids suchas for example, hydrogen halides, preferably as the chloride, sulfuricacid, oxalic acid and the like, such as for example, piperidinehydrochloride. The reaction can be suitably carried out at a temperaturerange of from 0° to about 80° C. A preferred temperature range for thisreaction is 15°-40° C. While the ratio of reactants used for thereaction is not critical, it has been found advantageous to useapproximately a 10:1 molar ratio of formaldehyde to keto acid and a0.1:1 to 1:1 molar ratio of amine to keto acid.

The reaction is best effected in a dimethylsulfoxide solvent whichfunctions both as a solvent for the reaction and also as adecarboxylating agent. Most advantageous results are obtained byallowing the compound of formula IV-f to decarboxylate in thedimethylsulfoxide solvent so as to form the corresponding anion andquench it immediately with the Mannich System formed by the addition offormaldehyde and primary or secondary amine salt. Aqueous formalin (37percent-40 percent) is a generally satisfactory source of formaldehydefor this reaction. Exemplary of the amines suitable for this reactioninclude heterocyclic amines such as morpholine, piperidine andpyrrolidine; monoamines such as methylamine, butylamine and benzylamine.An especially preferred amine for this reaction is piperidine. Otherpolar solvents such as, for example, dimethylformamide andhexamethylphosphoramide which are inert to the reactants may be employedin conjunction with the dimethylsulfoxide. The dimethylsulfoxide solventpromotes decarboxylation and anion formation at the bicyclic C-4position notwithstanding the known preferential tendency of thesecompounds to enolize in the direction of the bicyclic C-6 position.

In another aspect of this invention in accordance with Reaction SchemeA, compounds of Formula IV-c may be prepared by alternate process routes(3→9), (5→7→9), (5→10), and (5→6→8).

Thus, the compounds of formula IV-e can be prepared in accordance withStep (5) from the β-keto acids of formula IV-f in excellent yieldsemploying an organic or inorganic acyl halide preferably thionyl halide,e.g., thionyl chloride; phosphorus trihalide, preferably phosphoroustrichloride and phosphorous pentahalide, preferably phosphorouspentachloride. Thionyl chloride is particularly convenient since theby-products formed are gases and can be easily separated from the acidchloride. Any excess of the low boiling thionyl chloride can be easilyremoved by distillation. This substitution reaction was successfullyeffected notwithstanding the known prior art [ef., C. B. Hurd et al., J.Am. Chem. Soc. 62, 1548, (1940)] which teaches the inability to prepareβ-keto acyl halides by conventional reaction techniques from thecorresponding β-keto acids. The reaction is suitably conducted at atemperature of from 0° C to the boiling point of the solvent. Suitablesolvents for the conversion are thionyl chloride (neat) or in an inertorganic solvent such as, for example, benzene, toluene, hexane,cyclohexane and the like.

4-Carbonyl halide indanone compounds of formula IV-e, can be convertedto the corresponding esters of formula IV-d by means known in the art.Preferred esters are those wherein R'₃ is lower alkyl, especially methyland ethyl. The esters can be conveniently obtained by reacting thehalide with an alkali alkoxide, e.g., sodium methoxide in a solvent suchas, for example, lower alcohol, e.g., methanol and the like.Alternatively, the esters of formula IV-d may be obtained by reactingthe halide with carbonyl diimidazolide in tetrahydrofuran solvent, thenfurther reacting the thus obtained product with the desired aliphatic oraryl alcohol, e.g., phenol, methanol, ethanol and the like at roomtemperature to the reflux temperature of the solvent in, for example,tetrahydrofuran to obtain the desired ester.

As a further alternate wherein it is desired to prepare 4-alkoxycarbonyl indanones of formula IV-d, the conversion can be effected bytreatment of the acids of formula IV-f with an ethereal solution of adiazoalkane such as diazomethane by known means. The reagent is a yellowgas and small quantities can be prepared conveniently prior to use inthe form of a solution in ether. When the yellow ethereal solution isadded in portions to a solution or suspension of the acid in ether atroom temperature, nitrogen is evolved at once and the yellow color isdischarged. When the yellow color persists, which is an indication thatexcess diazomethane has been added, the solution can be heated, e.g., ona steam bath to expel excess reagent. Since the only by-product is agas, a solution of the desired ester in ether results.

The esters of formula IV-d can also be prepared by first esterifying theunsaturated acid compounds of formula VIII to compounds of formulaVIII-a in accordance with Reaction Scheme A by the aforementionedmethods and then catalytically hydrogenating this unsaturated ester. Thesteric course of this hydrogenation proceeds so as to yield theC/D-trans-hydrogenated product. Thus, an identical product of thestructure of formula IV-d with C/C-trans-ring fusion is obtained in asimilar manner to the case wherein the acid of formula VIII is employeddirectly as the starting reactant for the hydrogenation step. Thebicyclic C/D-trans-structure obtained by the catalytic hydrogenation ofthe ester may be explained (although applicant is not bound by thistheory) by postulating a chelated dienol ester intermediate formed fromthe non-enolic unsaturated β-keto ester on the surface of the catalyst.However, it should be noted that the rate of catalytic hydrogenation ofthe β-keto acid of formula VIII was approximately four times as rapid aswas the case when the corresponding β-keto ester was employed as thereactant. However, hydrogenation of the ester employing approximatelythree times the amount of catalyst employed in the case of the acidunder identical reaction conditions resulted in an approximately equalhydrogenation rate.

The β-keto aldehydes of formula IV-b can be prepared from the acidhalides of formula IV-e in accordance with Step (6) of Reaction Scheme Aemploying a reducing agent such as, lithium aluminumtritertiarybutoxyhydride. The reaction can be carried out in an inertaprotic organic solvent such as, ethers, e.g., tetrahydrofuran andhydrocarbons, e.g., toluene and hexane at a temperature range of -10° to-60° C., preferably between the temperature range of -20° and -40° C.When the reaction is carried out within the aforesaid definedtemperature ranges, selective reduction of the acid halide can beeffected without attacking the free keto group on the 5-position of theindane of formula IV-e. An alternative method of transforming the acidhalide to the corresponding aldehydes can be accomplished by thecatalytic hydrogenation of the acid chloride by the Rosenmund Reaction.The technique introduced by Rosenmund consists in adding a small amountof a poisoning agent containing sulfur to the hydrogen catalyst system.

The indanones of formula IV-c wherein R₄, Z and m are as defined asaforesaid can be conveniently prepared in accordance with Steps (8), (9)and (10) of Reaction Scheme A depending upon the nature of X, from theesters of formula IV-d, the acid halides of formula IV-e or thealdehydes of formula IV-b.

Suitable requirements for the leaving group as defined by X in thecomponents of formula IV-c are that it should function efficaciously inthis process aspect, that is, that it be a suitable leaving group forthe process of the present invention. Suitable groups which may beemployed to form leaving groups are lower alkyl-aryl sulfonyloxy groupssuch as, for example, tosyloxy; arylsulfonyloxy groups such as, forexample, benzene sulfonyloxy; lower alkyl sulfonyloxy groups such as,for example, mesyloxy (methane sulfonyl); lower alkyl sulfinyloxy;halogen; an acyloxy radical derived from an organic carboxylic acidhaving 1 to 7 carbon atoms such as lower alkanoic acid, e.g., aceticacid and butyric acid; aryl carboxylic acids such as p-phenylbenzoicacid and benzoic acid and cycloalkyl carboxylic acids such ascyclopentyl carboxylic acids. Other suitable leaving groups may beselected from the group consisting of ##EQU5## wherein each of R₂₀ andR₂₁ is independently selected from the group consisting of lower alkyl,aryl and hydrogen, and R₂₀ and R₂₁ when taken together to the nitrogenatom to which they are joined form a 5- or 6-membered heterocyclic ringstructure. Thus, the ##EQU6## amino grouping represents secondary andtertiaryamino radicals. It includes monoalkylamino radicals, such as,for example, methyleneamino and butylamino; dialkylamino radicals suchas, for example, dimethylamino and dipropylamino, heterocyclic aminoradicals, such as, for example, pyrolidino, piperidino, morpholino and4-methyl-piperizino. The amino radical ##EQU7## may also be employed asa leaving group in a modified form by alkylation by known means with asuitable organic ester such as, for example, lower alkyl halide, e.g.,methyl chloride or a hydrohalic acid such as, for example, hydrogenchloride to form the corresponding quaternary ammonium salt of theformula ##EQU8## wherein R₂₀, R₂₁ and Y are as defined aforesaid and R₂₂is a cation from the organic ester.

Generically, the preferred leaving groups are tosyloxy and mesyloxyalthough depending on the steroidal end products being prepared, otherleaving groups as exemplified above may be more preferable.

The compounds of formula IV-c wherein the leaving group X is loweralkyl-sulfonyloxy, e.g., mesyloxy or lower alkyl aryl-sulfonyloxy, e.g.,tosyloxy may be conveniently prepared from the esters of formula IV-d inaccordance with Step (9) of Reaction Scheme A by a reaction sequencewhich comprises first protecting the 5-oxo moiety on the indanone,reducing the ester group to the corresponding 4-hydroxy methylenederivative, removing the protecting group before or after conversion tothe desired derivative of formula IV-c. Protection can be effected byconverting the free oxo group to a cyclic ketal, e.g., a dioxolane ringsystem by reaction with a suitable lower alkylenedioxy containingcompound, e.g., ethylene glycol or to an open ketal with for example,tri-lower alkyl orthoformates. The free oxo moiety can be regeneratedafter reduction of the 4-ester compounds of formula IV-d to thecorresponding 4-hydroxy methylene compounds. A preferred protectinggroup is the dimethoxy derivative which can suitably be obtained byetherification with trimethyl orthoformate. The thus protected 4α-estercan be reduced employing for example, a suitable reducing agent such as,diisobutyl aluminum hydride to yield the 4-hydroxy methylene compound ofthe formula ##SPC8##

wherein R₄, Z and m are as defined aforesaid.

Alternatively, the ester of formula IV-d in the protected form obtainedas described above may be reduced to the alcohol of formula IV-c-1 usingan alkali metal reducing agent such as sodium metal and lower alcohol orlithium aluminum hydride. Compounds of formula IV-c wherein the leavinggroup X is lower alkyl sulfonyloxy or lower alkyl-arylsulfonyloxy can beprepared by esterification with an organic sulfonylhalide such as, forexample, toluenesulfonyl halide, especially, p-toluenesulfonyl chlorideto prepare the tosyloxy derivative or lower alkyl sulfonyl halides,especially methane sulfonyl chloride to prepare the mesyloxy derivative.The above reactions can be suitably conducted at a temperature range of-10° to +10° C in the presence of an organic base such as, for example,pyridine by methods known in the art. The corresponding sulfonic acidsmay also suitably be employed to effect the esterification in lieu ofthe sulfonyl halide. Leaving groups wherein X is lower alkyl sulfinyloxymay be obtained in an analogous manner to that above by employing thecorresponding sulfinyl halides.

Leaving groups wherein X is defined by the grouping ##EQU9## wherein R₂₀and R₂₁ are defined as aforesaid can be conveniently obtained from theacid halides of formula IV-e in accordance with process route (10) ofReaction Scheme A by a reaction sequence which comprises the steps of(a) reacting the compounds of formula IV-e with a primary or secondaryaliphatic or aromatic amine of the formula ##EQU10## by known means toform the corresponding amide of the formula ##SPC9##

wherein R₄, Z, m and R₂₀ and R₂₁ are as defined aforesaid;

(b) protecting the 5-oxo group of the compounds of formula IV-c-2 byforming the 5-ketal analog in a manner similar to that previouslydescribed; (c) reducing the amide with a suitable reducing agent suchas, for example, diborane or lithium aluminum hydride in an ethersolvent such as, for example, tetrahydrofuran which upon removal of theprotecting group by means of dilute mineral acid yields a compound ofthe formula: ##SPC10##

wherein R₄, Z, m, R₂₀ and R₂₁ are as defined aforesaid.

The compounds of formula IV-c-3 can be converted to their quaternarysalt adducts by alkylation with for example, a lower alkyl halide suchas methyl chloride.

Leaving groups wherein X is defined by the grouping ##EQU11## wherein atleast either R₂₀ and R₂₁ is hydrogen, may also be prepared from thealdehydes of formula IV-b in accordance with process route (8) ofReaction Scheme A by selective condensation with a primary amino of theformula --H₂ NR₂₀ to form by known means the novel imino Shiff Baseintermediate of the formula ##SPC11##

wherein R₄, Z m and R₂₀ are as defined aforesaid.

The ald-imines of formula IV-c-4 can be conveniently reduced withhydrogen and Raney Nickel to the desired secondary amines.

Leaving groups wherein X is defined as halogen may be convenientlyobtained from the alcohols of formula IV-c-1 by reaction with forexample, hydrogen halides, e.g., hydrogen chloride, phosphorous halidesor thionyl chloride by means known in the art. Leaving groups wherein Xis acyloxy as defined aforesaid may be suitably obtained from thecompounds of formula IV-c-1 by reaction with the desired organiccarboxylic acid in the presence of a mineral acid such as sulfuric acidor hydrochloric acid at reflux temperature by means known in the art.

In another aspect, the process of this invention relates to thepreparation of compounds of the formulae I, II and III by reaction of aβ-keto ester or other analog of formula V with compounds of formulaeIV-c and IV-a in accordance with Reaction Scheme B. It should beappreciated that compounds of the formulae IV-a and IV-c can be usedinterchangeably in all of the hereinafter process reactions. ##SPC12##

wherein R₄, m, X, Z, R₂₅, R₂₃, R₁₁ and R₁ are as defined aforesaid.

The process of this invention in this aspect, comprises employing thebicyclic indanone derivatives of formulae IV-a and IV-c prepared asaforesaid and reacting them with certain subgeneric compoundsencompassed by generic compounds of the formula V-b in accordance withprocess route (11) of Reaction Scheme B to prepare the benz[e]indenecompounds of formula I. Alternatively, for other subgeneric compoundsencompassed by generic formula V-a in accordance with process routes(12) and (13) of Reaction Scheme B, the steroids of formulae II and IIImay be prepared. Thus, for certain compounds subgeneric to formula V,viz -- formula V-b as defined below, the tricyclic benz[e]indenes offormula I may be prepared by means of the building in an annulationreaction steroidal ring B. Alternatively, for certain other compoundssubgeneric to formula V-a as defined hereinafter, the steroids offormulae II and III may be prepared by building by means of compounds offormula V-a, steroidal rings A and B. Thus, the keto compounds offormula V are employed as one of the starting reactants for thepreparation of the tricyclic compounds of the formula I or thetetracyclic compounds of formulae II and III. However, it will beappreciated that the length of the carbon chain varied as exemplified byformulae V-a and V-b below, depending on which class of end products aresought to be prepared. Thus, the β-keto esters and analogs thereof offormula V-a below, are employed wherein it is desired to prepare thetetracyclic steroids of formulae II and III. ##EQU12## wherein R₇, R₁₅,B, R₂₅ and R₂₆ are defined as aforesaid.

The β-keto esters and other analogs of formula V-a can be prepared inaccordance with Reaction Scheme C below in which a specific embodimentis illustrated. The β-keto esters of formula V-a-1 can be prepared fromthe hexanoic esters of formula X via process route (a) by reaction withbase, preferably, lithium hydroxide in a lower alcohol solvent, e.g.,ethyl alcohol at the reflux temperature of the solvent to form the saltof the acid by saponification of the ester. Subsequent reaction of thethus obtained salt with equimolar quantity of an organo metalliccompound, preferably, methyl lithium in tetrahydrofuran in the presenceof a minute amount of triphenylmethane yields the compounds of formulaXII. In effecting the conversion, R₁₅ should be in a protected ketoform, e.g., ketal, the conversion to which has been herein beforedescribed. Alternatively, the compounds of formula XII can be preparedin accordance with Reaction Scheme C, via process routes (b) and (c) byreacting the compounds of formula X with a lower alkyl sulfinylmethylene compound, e.g., methyl sulfinyl carbanion [cf., E. J. Coreyand M. Chaykovsky, J. Am. Chem. Soc. 86, 1639 (1964 )] to yieldintermediates of formula XI. The compounds of formula XI can if desired,be oxidized to the sulfonyl derivatives witih an oxidizing agent suchas, for example, potassium permanganate. Reduction of the thus obtainedsulfoxides of formula XI with a reducing agent, preferably, aluminumamalgam, yields compounds of formula XII. The compounds of formula XIIcan be converted to the β-keto esters of formula V-a-1 via a ClaisenCondensation with a carbonate of the formula

    (R.sub.5).sub.2 CO.sub.3

wherein R₅ is aryl or lower alkyl

in accordance with process route (e). The preferred condensing agent issodium hydride although alkali lower alkoxides, e.g., sodium alkoxidemay also be suitably employed. The reaction is conveniently conducted inan ether solvent such as, for example, diethylether or tetrahydrofuran,the former being preferred at the reflux temperature of the solvent.##EQU13## wherein R₁₅, R₂₅, R₂₆, and R'₃ are defined as aforesaid and R₅is lower alkyl or aryl.

Illustrative of the β-keto ester and other analog compounds of formulaV-a which may be employed as starting reactants wherein it is desired toprepare the steroids of formulae II or III include6-(2-methyl-1,3-dioxolan-2-yl)-3-oxohexanoic acid ether ester;6-(2-ethyl-1,3-dioxolan-2-yl)-3-oxohexanoic acid ethyl ester;3,7-dioxo-octanoic acid methyl ester;6-(2-methyl-1,3-dioxolan-2-yl)-3-oxohexanoic acid propyl ester;3,7-dioxodecanoic acid ethyl ester;1-methylsulfinyl-5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone and thelike. By referring to the general formula IV, it can be thus appreciatedthat when it is desired to prepare the steroids of formula XVII, theselections of the variables of formula V should be as follows: R₆ is##EQU14## and R₂₅, R₂₆, R₁₅ and B are defined aforesaid.

The β-keto esters and other analogs of formula V-b below, are employedwherein it is desired to prepare the tricyclic compounds of formula I##EQU15## wherein R₆ and B are defined as aforesaid.

The compounds of formula V-b, for example, ethyl propionyl acetate, maybe prepared in a similar manner to the compounds of formula V-a inaccordance with process step (e) by employing in Reaction Scheme C (theClaisen Condensation Step) butanone in lieu of the compounds of formulaXII.

Exemplary of the β-keto ester and other analogs of formula V-b which maybe employed as starting reactants wherein it is desired to prepare thetricyclic compounds of formula I include ethyl propionyl acetate, methylpropionyl acetate, ethyl aceto acetate, ethyl butyro acetate, butyroacetonitrile, acetoacetonitrile, 1-methyl-sulfinyl-2-butanone and1-methyl-sulfonyl-2-pentanone.

While certain groups exemplified by the definition of the term B havebeen illustrated in the β-keto ester and other analogs of formulae V-aand V-b, it is to be understood that any other equivalent electronwithdrawing group or groups of electrophilic nature can function aswell. All that is required for the B segments of the molecule for theprocess of the reaction of the compounds of formula IV with thecompounds of formula V is that it function efficaciously in this processaspect, that is, that it be a suitable electron withdrawing group so asto activate the hydrogen atom on the methylene group next adjacent tothe carbonyl group. Preferred electron withdrawing groups are the alkoxycarbonyl esters, especially ethoxy carbonyl. The β-keto nitriles, e.g.,aceto-acetonitrile of formula IV-b may be prepared by reaction ofacetonitrile phenyllithium and diethylamine at a temperature range of-10° C to +10° C and hydrolyzing in dilute acid the thus obtained imineintermediate to the desired product [ef., Ann. 504, 94 (1933)]. Thecompounds of formula V-a and V-b wherein B is defined as lower alkylsulfinyl methylene and lower alkyl sulfonyl methylene can be readilyprepared from the esters of formula V-a-1 in a similar manner to thatemployed in process step (b) of Reaction Scheme C.

In a further aspect, the synthesis of the present invention relates tothe preparation of steroids of the formulae II and III in accordancewith Reaction Scheme B by means of reacting a carbon chain of theformula V-a with a bicyclic compound of the formulae IV-a or IV-c. InReaction Scheme D, the numbers are assigned to Roman numerals foridentification. Schematically, the sequence of reactions involved in thesynthesis of a specific embodiment, namely, 19-nortestosterone isillustrated. ##SPC13##

In the Michael addition, process step (a) of Reaction Scheme D, theprecursors to the steroidal A and B rings are built up in a singleannulation reaction. The reaction is conducted in the presence of a basesufficiently strong to form the anion of the β-keto ester. Exemplarybases are for example, alkali metal lower alkoxides such as sodiummethoxide, sodium ethoxide, potassium methoxide, potassium tertiarybutoxide and the like; alkali metal hydroxides such as sodium hydroxideand the like; alkali metal hydrides such as sodium hydride, lithiumhydride and the like; alkali metal amides such as lithium amide, sodiumamide and the like; methyl sulfinyl carbanion (i.e., the anion fromdimethyl sulfoxide). Especially preferred are the alkali metal loweralkoxides. The reaction can be conducted at a temperature range of fromabout -5° C to about 100° C. However, it is especially advantageous toconduct a reaction within a temperature range of from 0° to 25° C.Moreover, the reaction is suitably conducted in the absence of oxygenfor example, in an atmosphere of inert gas such as nitrogen or argon. Itis convenient to conduct the reaction in the presence of an organicsolvent inert to the reactants as well as the intermediates of formulaXVI. Such solvents are for example, dimethylformamide, dimethylsulfoxideand aromatic hydrocarbons, such as, for example, benzene, toluene andxylene. Other suitable solvents include the ethers such as diethylether,tetrahydrofuran and the like and lower alkanols such as methanol,ethanol and the like. The concentration of reactants is not critical butit is preferred to use a 1:1 molar ratio of reactants of formulae IV-a-1and V-a-3. One may add the reactant of formula V-a-3 to a reactionmixture already containing the bicyclic indanone of formula IV-a-1.However, the reaction can also be effected by placing all the reactantssubstantially together or preferentially the reactants of formula IV-a-1can be added to a mixture containing the reactants of formula V-a-3.When employing as a starting reactant, the compounds of formula IV-a inlieu of the reactants of formula IV-c-1, the same process conditions areemployed and products obtained although the reaction does notnecessarily have to proceed by way of a Michael addition mechanism. Thesidechain of the reaction intermediate XVI assumes the thermodynamicallyfavorable equatorial configuration under the equilibrating reactionconditions. The alpha orientation of the sidechain is extremelyimportant for the construction of ring B with the properstereochemistry. No ring closure occurred at this stage because of thepreferred enolization of the keto group towards the ester function.Following the Michael addition of the β-keto ester of formula V-a-3 tothe bicyclic C/D-trans-indanone of formula IV-b-1, the thus obtainedcompound of formula XVI is saponified to remove the ester group andcyclized in accordance with process step (b) of Reaction Scheme D. Thecyclization should be effected under reaction conditions which do notcleave the cyclic ketal protecting group. Exemplary basic cyclizationreagents are for example, a dilute aqueous solution of alkali oralkaline metal hydroxides such as for example, sodium hydroxide, lithiumhydroxide, calcium hydroxide and the like. The cyclization is suitablyconducted in an inert organic solvent such as for example, hydrocarbons,e.g., benzene, toluene and ethers, e.g., tetrahydrofuran. Thecyclization can be conducted at room temperature or above roomtemperature but as a matter of convenience, it is preferable to conductthe reaction at about room temperature. The ester group of the bicyclicintermediate of formula XVI can be removed by saponification of theester in accordance with Step (b) of Reaction Scheme D to afford thecorresponding acid of the formula XVII (after acidification) anddecarboxylation to compounds of the formula XVII-1 for example, inrefluxing toluene under an inert atmosphere such as for example,nitrogen in accordance with Step (c) of Reaction Scheme D. For othercases wherein the electron withdrawing group of formula V (B) is otherthan ester, e.g., for example, lower alkyl sulfinyl methylene or loweralkyl sulfonyl methylene, the removal of the grouping can be effected byreduction with a reducing agent such as, for example, aluminum amalgam.For cases wherein the electron withdrawing group is nitrile, thereaction can be suitably conducted in an analogous manner to thatwherein the electron withdrawing group is an ester as discussed above.

The hydrogenation of the Δ ⁹(10) -double bond of the compounds offormula XVII-a to the compounds of formula XVIII can be effected inaccordance with Step (d) of Reaction Scheme D in a lower alcohol solventsuch as, for example, ethyl alcohol in the presence of a base,preferably, triethylamine. 19-Nortestosterone can be obtained from thecompounds of formula XVIII by hydrolysis of the tertiarybutyl ethercyclization by refluxing in a mineral acid such as, hydrochloric acid orsulfuric acid in a lower alkanol solvent such as methanol in accordancewith Step (e) of Reaction Scheme D.

It should be noted that the process steps exemplified in Reaction SchemeD can be utilized to prepare norgestrel. This can be effected bypreparing the 7aβ-ethyl analogs of formula IV-a-l as described on page 9of the instant specification employing the reaction steps (a), (b), (c),(d) and (e) of Reaction Scheme D followed by oxidation utilizing forexample, Jones Reagent and ethinylation in accordance with proceduresdescribed on page 49 of the instant application. It will be furtherappreciated that by employing the optically active 7aβ-ethyl enantiomerof formula IV-a-l of Reaction Scheme D, one can prepare optically activenorgestrel.

It will be appreciated that this aspect of the process of the inventionfor the synthesis of steroids of the formula II of which19-nortestosterone is a specific exemplar as set forth in ReactionScheme D, can be modified so as to yield other pharmaceutically valuablesteroids of formula II, well known in the art, wherein R₂ is other thenhydrogen, e.g., lower alkyl by selectively alkylating the Δ⁹(10)-compounds of formula XVII-l with a lower alkyl halide in the presenceof a strong base, preferably lithium in liquid ammonia at temperaturesin the order of -40° C in an inert solvent such as, for example, diethylether by means known in the art.

Moreover, when R₁₅ of the β-keto ester or other analogs thereof of theformula IV-a is oxo and not in a protected ketal form, Δ⁴, Δ⁹(10)-steroids of formula III in lieu of the steroids of formula II will beproduced in accordance with Reaction Scheme E. Thus, in a specificembodiment exemplified in Reaction Scheme E, steroids encompassed by thegenus of the formula III are prepared. The dione ester of the formulaV-a-4 is reacted with the methylene ketal of formula IV-a-l inaccordance with Step (a) in the presence of an alkali alkoxide such as0.1 N sodium methoxide in a methanol solvent using a temperature rangeof 0°-20° C to yield the substituted trione of formula XVI-a. Thecompound of formula XVII-a in accordance with Step (b) of ReactionScheme E can be hydrolyzed and ring closed using a hydrogen halide acidsuch as hydrogen bromide in an acetone solvent at a temperature ofapproximately 20° C to yield the acid compound XVII-a. Decarboxylationof compound XVII-a in refluxing toluene in accordance with Step (c)yields compound XVII-l-a. The diene steroids of the formula III-a can beobtained in accordance with Step (d) of Reaction Scheme E by cyclizingthe compound of formula XVII-l-a using an alkali alkoxide preferablypotassium t-butoxide in benzene. The 17-hydroxy diene steroids offormula III-b are obtained in accordance with Step (e) of ReactionScheme E by refluxing in methanol in the presence of acid, preferablyhydrogen chloride. ##SPC14##

The keto compound XVII-l of Reaction Scheme D can also be converted tosteroids of the formula XVII-l-a via mild hydrolysis of the ketal moietyemploying 0.1 N hydrochloric acid in a solvent such as tetrahydrofuranat a temperature of approximately 20° C in accordance with Step (f) ofReaction Scheme E. Steroids of Formula III can be converted topharmaceutically valuable estrogens by known means (cf. Velluz et al.,Angewandte Chemie 72, 725 (1960).

In a further aspect, the present invention relates to the preparation ofΔ⁴, Δ⁹(10) -steroids of the formula III by reacting a vinylogous betaketo ester or other analogs of the formula ##SPC15##

wherein B' is defined as aforesaid

with compounds of the formula IV-a and IV-c. ##SPC16##

A preferred value of B' is lower alkoxy carbonyl. Especially preferredis methoxy carbonyl and ethoxy carbonyl. Thus, in a specific embodimentexemplified in Reaction Scheme F, diene steroids of the formula III-bare prepared. The vinylogous beta keto ester of formula VI-a is reactedwith the methylene ketone of formula IV-a-l in accordance with Step (a)of Reaction Scheme F in the presence of an alkali lower alkoxide,preferably 0.1 N sodium methoxide in a lower alcohol solvent,preferably, methanol or ethanol, at a temperature range of 0° to 20° Cyielding the dione of formula XXIII. The diene steroid of formula III-bcan be conveniently obtained from the compound of formula XXIII bycyclization using refluxing mineral acid, preferably, l-N-hydrochloricacid in a lower alcohol solvent, preferably methanol.

In still another aspect of this invention, compounds of the formulaIV-f, in Reaction Scheme A, can be converted to compounds of the formulaXXIII below, which are subgeneric to the compounds of formula IV##SPC17##

wherein R₄, Z and m are as defined aforesaid

by decarboxylation in a refluxing solvent such as, for example,tetrahydrofuran or toluene with or without a strong mineral acid, e.g.,hydrochloric acid. The novel C/D-trans bicyclic indanone of compounds offormula XXIII are themselves useful intermediates in a total steroidalsynthesis by employing, e.g. the methods described by R. E. Ireland andM. Chaykovsky, J. Org. Chem. 28, 748 (1963) the compounds of formulaXXIII can be converted to their Δ⁶ acid analogs by abromination-dehydrobromination procedure. The Δ⁶ -C/D trans indanonescan be converted by methods described in the above cited reference tothe tricyclic compounds of the formula I which in turn can be convertedto pharmaceutically valuable steroids by procedures hereinafterdescribed.

In a further aspect, the synthesis of the present invention relates inaccordance with Step (11) of Reaction Scheme B to the preparation of2,3,3a,4,5,7,8,9,9a,9b-decahydro-3a-alkyl-7-oxo-lH-benz[e]indenes and4,4aβ,4bα,5,6,7,8,8a,9,10-decahydro-8aβ-alkyl-3H-phenanthrene-3-oneswhich contain in the 3-position and 8-position, respectively, an oxosubstituent or a β-OR₂ moiety wherein R₂ has the meaning given in thetext accompanying formula I. Many members of this class of knowncompounds which are valuable intermediates in the synthesis of steroids,for example, benz[e]indene derivatives contain asymmetric centers atpositions-9a,9b,3a and also at the 3-position if the substituent thereatis other than oxo. Thus, of the 3-oxo compounds, there are eightpossible different stereoisomers, whereas of the compounds containing a3-OR₂ substituent, there are possible sixteen stereoisomers.

In a preferred embodiment of this aspect, the synthesis relates to thepreparation of the 9aβ,9bα,3aβ-stereoisomers of the benz[e]indeneseries, its optical antipode and racemate thereof and in the case wherethe 3-substituent is other than oxo, the 9aβ,9bα,3aβ,3β-stereoisomer,its optical antipode and the racemate thereof. The correspondingphananthrene-2-ones, i.e., 4aβ,4bα,8aβ-stereoisomers may also beprepared. The especially desired end-products of the synthesis of thisinvention are the (-)-enantiomers of the formula ##SPC18##

wherein R₁, R₄, and Z and m are as defined aforesaid.

The compounds of formula I can be obtained by commencing the synthesisof this invention with an optically pure starting material of formula IVor by commencing the synthesis of this invention with a racemic (i.e.,dl) starting material of the formula IV and effecting resolution at anyintermediate stage or after the desired end-product of formula I hasbeen obtained as the racemate.

Referring to Reaction Scheme G, wherein the compounds are assigned Romannumerals for identification schematically, the sequence of reactionsinvolved in the synthesis of a specific embodiment, namely, thebenz[e]indenes of formula I-a are illustrated. Thus,ethylpropionylacetate is reacted with a compound of formula IV-c-lwherein the leaving group X exemplified is mesyloxy (compounds offormula IV-a-l can also suitably be employed) to yield compounds offormula XV in accordance with Step (a). Reaction conditions employed forthis conversion are identical with that exemplified hereinabove inprocess step (a) of Reaction Scheme E for the preparation of compoundXVI. Compound of formula I-a is obtained in accordance with process step(b) via cyclization which includes an internal aldol condensation anddehydration using a strong mineral acid, e.g., 2N-hydrochloric acid in alower alcohol solvent, e.g., methanol, at the reflux temperature of thesolvent. The conversion of compounds of the formula XV of ReactionScheme G to compounds of the formula I-a can also be conducted underreaction conditions employed in Steps (b), (c) and (e) of ReactionScheme D. ##SPC19##

As indicated above, the2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-3aβ-alkyl-7-oxo-lH-benz[e]indenes andthe 4,4aβ,4bα,5,6,7,8,8a,9,10-decahydro-8aβ-alkyl-3H-phenanthren-2-onesof formula I obtained by the process of this invention are useful asintermediates in the formation of the tetracyclic steroid nucleus inaccordance with Reaction Scheme F. The benz[e]indenes and thephenanthren-2-ones are a known class of compounds. The benz[e]indenes,for example, can be converted into the tetracyclic steroid nucleus bycondensing the 7-oxo-benz[e]indene with for example, methyl-vinyl ketoneor 1,3-dichloro-2-butene according to methods known per se. The patentliterature contains many references which are illustrative of methods toeffect conversion of the tricyclics of formula I to known steroids ofwhich U.S. Pat. Nos. 3,115,507; 3,120,544; 3,128,591; 3,150,152 and3,168,530 are exemplary.

The ultimate utility of the tricyclic intermediates depends on thenature of R₁ and R₄. For example, compounds wherein R₁ is hydrogen maylead to either 19-nor steroids (Velluz et al., Angewandte Chemie 72,725, (1960); or alternatively to 10α-19-nor-steroids (French Pat. No.1,360,55) depending upon the reaction conditions. Further, thetricyclics wherein R₁ is hydrogen may be converted into19-nor-retro(9β,10α)-steroids (Velluz et al., Tetrahedron Suppl. 8, PartII, 495 (1966) and estrogens, viz -- compounds having an aromatic A ring-- e.g., estradiol (Velluz et al., Angewandte Chemie 72, 725 (1960). Onthe other hand, compounds wherein R₁ is alkyl may lead to compounds ofthe 9α,10α-series (Velluz et al., Angewandte Chemie 77, 185, (1960) oralternatively to compounds of the retrosteroid series viz -- thosehaving inverted centers of asymmetry at positions C₉ and C₁₀, i.e., the9β,10α-steroids (Belgium Pat. No. 663,193). Compounds wherein R₁ islower alkyl may be obtained wherein R₆ of the compounds of formula V-bis lower alkyl (other than methyl).

As illustrated by the following Reaction Scheme H, in the first step ofthis reaction, the cyclo-olefin I may be hydrogenated to the tricycliccompound XIX. The reaction is preferably effected with a noble metalcatalyst, e.g., a palladium-charcoal or a lower-rhodium charcoalcatalyst. In formula XIX, R₁ represents hydrogen or lower alkyl. Thus,compounds of formula I wherein R₁ represents hydrogen or alkyl can behydrogenated to the compounds of formula XIX. The conversion ofcompounds of formula I to compounds of formula XIX and of the latter tocompounds of formula XXII are described in greater detail in BelgiumPat. No. 663,197.

Tricyclic compounds of formula I for values wherein R₁ is hydrogen maybe converted by means known in the art to compounds of formula XXIwherein R₁ is hydrogen viz -- steroids of the 19-nor-10α-series.Further, the tricyclic compounds of formula I wherein R₁ is hydrogen maybe alternatively converted to compounds of formula II viz -- the normalsteroids of the 9α,10β-(normal- 19-nor series). This is described morefully in Angewandte Chemie 77, 185 (1965), Velluz, Valls and Nomine andAngewandte Chemie 72, 725 (1960), Velluz et al. ##SPC20##

A preferred procedure for converting tricyclic compounds of formula Iwherein R₁ is hydrogen to normal steroids of the 9α-19-nor series offormula II can be effected by reacting the tricyclic compounds with4-halo-2-alkoxy butane wherein the halogen is preferably selected fromthe group consisting of chlorine, bromine or iodine. For example, atricyclic compound of formula I such as2,3,3a,4,5,7,8,9aβ,9bα-decahydro-3aβ-ethyl-3-oxo-7-oxo-lH-benz[e]indenemay be reacted with for example, 4-chloro-2-tertiarybutoxy-butane in asuitable solvent such as, for example, dimethylformamide ordimethylsulfoxide under a nitrogen atmosphere in the presence of a basesuch as, for example, sodium hydride or potassium tertiarybutoxide at atemperature range of between 15° and 100° to yield the intermediate10-[3-tertiarybutoxy-butyl]-13-ethyl-19-nor-desA-androst-9-ene-5,17-dione. This latter compound can be converted to norgestrel byprocedures described more fully in U.S. patent application of GabrielSaucy, Ser. No. 679,989, filed on Nov. 2, 1967.

4-Halo-2-tertiarybutoxy may be prepared from 4-halo-2-butanol byreaction of the latter compound with isobutylene in the presence of amineral acid such as sulfuric acid or hydrochloric acid at roomtemperature.

The tricyclic compounds of formula I for values wherein R₁ is alkyl maybe converted by methods known in the art to compounds of formula XXIIviz -- steroids of the "retro" series via catalytic hydrogenationcompounds of the formula XIX and base catalyzed reaction with forexample, methyl vinyl ketone.

Compounds of formula I can also be directly reacted with for example,methyl vinyl ketone yielding a 5hydroxy-tetracyclic compound of formulaXX. These latter compounds can then be subjected to dehydration followedby hydrogenation or to hydrogenation followed by dehydration to yield a9β,10α- or 10α-steroids of formulae XXI and XXII. These procedures aredescribed in greater detail in Netherlands Octrooiaanvrage No.6,412,939. Still other methods of utilizing compounds of formula I aredescribed in the literature or in the patents.

Compounds of formula I when converted into compounds of formula IIwherein R₄ is ethyl and R₁ is hydrogen and Z is carbonyl can beselectively alkynylated by a suitable organic metallic acetylideaffording norgestrel (13β-ethyl-17α-ethinyl-17-hydroxy-gon-4-ene-3-one).The latter compound can also be prepared according to Reaction Scheme D(cf. Page 39 herein). Exemplary of the suitable alkynylating agents toeffect conversion to norgestrel are the alkali acetylides such aslithium acetylide, potassium acetylide, sodium acetylide, etc. Thereaction is carried out in the presence of liquid ammonia in suitablesolvent systems such as benzene or toluene. The alkynylation is effectedpreferably at the reflux temperature of the reaction medium althoughtemperatures from -60° to -30° are suitable. Exemplary of other suitablereagents to effect the acetylenic addition are ethylaminediamine complexin dimethylformamide solvent and Grignard analogs such as mono and bisacetylene-magnesium halides by means known in the art.

Further, the 19-nor-compounds of formula II, wherein R₄ is propyl areovulatory inhibitors (cf., Tetrahedron Letters 127 (1961), Velluz,Nomine et al.). Additionally, compounds of formula I wherein R₄ ismethyl and R₁ is hydrogen have been converted to the series of formulaII, specifically, 19-nortestosterone acetate, J. Org. Chem., 26, 3904(1961), L. J. Chinn and H. L. Dryden.

Moreover, compounds of formula I wherein R₄ is ethyl and R₁ is methyland m is equal to 2 can be converted to compounds of formula XXII, i.e.,18-homo-retrosteroids, specifically the acetyl derivatives of thepregnane series, which are progestational agents and are thus useful inthe treatment of fertility disorders. The 18-homo-retroandrostanes ofthis series have both anti-estrogenic and anti-androgenic activityeffecting the secretion of gonadotropic hormones. Hence, these compoundscan be used for example, in the treatment of gynecological disorders andas contraceptive agents.

The methods of this invention, as indicated above, result in thepreparation either of the desired optical enantiomer illustrated byformulae I and II or the racemate thereof. The optical antipodeillustrated by formulae I and II can be obtained either by resolution ofthe corresponding racemic end product or by resolution of racemicstarting material or, if racemic starting material is directly subjectedto the methods of this invention, resolution of any intermediateracemate. The present invention pvovides a facile synthesis foroptically active end products as a result of the fact that opticalspecificity is preserved throughout the synthesis as a result of thestereo selectivity of the individual process conversions exemplified inReaction Schemes A, B, C, D, E and F. Resolution can be effected byconventional resolution means known per se. For example, compounds inwhich the moiety represented by the symbol Z is hydroxy-methylene, or agroup convertible into hydroxymethylene such as carbonyl (convertible byreduction to hydroxymethylene) or an ether or ester of hydroxy-methylene(convertible by hydrolysis to hydroxy-methylene), can be resolved byreacting the compound containing the hydroxy-methylene moiety with adibasic acid to form a half-acid ester. If the dibasic acids are, forexample, dibasic-lower alkanoic acids such as oxalic acid, malonic acid,succinic acid, glutaric acid, adipic acid or the like, or an aromaticdibasic acid such as phthalic acid, the so-formed half-acid ester isthen reacted to form a salt with an optically active base such asbrucine, ephedrine or quinine and the resulting diastereoisomericproducts are separated. Alternatively, the hydroxy-methylene moiety canbe esterified with an optically active acid such as camphorsulfonic acidand the resulting diastereoisomeric esters can be separated. The opticalantipodes can be regenerated from the separated diastereoisomeric saltsand esters by conventional means.

The following examples are illustrative but not limitative of theinvention. All temperatures are stated in degrees Centigrade. Infrared,ultraviolet and nuclear magnetic resonance spectra where taken wereconsistent with stated structures. IR spectra where indicated were takenin chloroform. UV spectra where indicated were taken in ethyl alcohol.

EXAMPLE 1

A 0.5 weight percent solution of 1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-indane in absolute ethanol washydrogenated at atmospheric pressure and room temperature using a 10percent palladium/CaCO₃ catalyst. Hydrogenation was stopped after theuptake of 1 mole of hydrogen. The solution was then filtered andevaporated in vacuo to give a crude hydrogenation product. This crudeproduct was then subjected to hydrolysis by stirring and refluxing forsix hours with a 1:1 mixture of tetrahydrofuran and 2 N hydrochloricacid under a nitrogen atmosphere. The solution was then cooled by meansof an ice bath and neutralized with 5 N sodium hydroxide. The solventwas then evaporated in vacuo and the residue was extracted sequentiallywith ethyl acetate and then ether. The extract was washed with asaturated sodium chloride solution and then dried over sodium sulfate.Evaporation of the solvent in vacuo afforded a mixture of cis and transreduction products -- 39β,4,7,7a-tetrahydro-1β-hydroxy-7aβ-methyl-5(6H)indanone and 3aα ,4,7,7a-tetrahydro-1β-hydroxy-7aβ-methyl-5(6H)indanone which was analyzedby vapor phase chromatography and NMR. The vapor phase chromatographyconsisting of repeatedly subjecting the crude mixture of3aβ,4,7,7a-tetrahydro-1β-hydroxy-7aβ-methyl-5(6H)indanone and3aα,4,7,7a-tetrahydro-1β-hydroxy-7aβ-methyl-5(6H)indanone to vapor phasechromatography in 40 milligram portions on a Barber-Coleman Model 5072equipped with flame detection and a split ratio of 5:95. By thistechnique, 3aα,4,7,7a-tetrahydro-1β-hydroxy-7aβ-methyl-5(6H)indanone wasobtained as an oil. γ_(max) 3620, 3300-3550 and 1715 cm⁻ ¹ in theinfrared spectrum.

EXAMPLE 2

110 Mg. of purified trans alcohol3aα,4,7,7a-tetrahydro-1β-hydroxy-3aβ-methyl-5(6H)indanone was oxidizedby reacting with 0.175 ml. of 8 N chromium trioxide in sulfuric acid ina medium of 5 ml. of acetone under a nitrogen atmosphere at 10°C overapproximately a 5 minute period. The reaction mixture was quenched bythe addition of 5.0 ml. of ice water and the organic solvent was removedin vacuo. The aqueous solution was then extracted with a mixture ofethyl acetate and ether. The organic phase was washed with sodiumbicarbonate and a saturated sodium chloride solution. The extract wasdried over sodium sulfate and evaporated in vacuo to give the crudeoxidation product 3aα,4,7,7a-tetrahydro-7aβ-methyl-1,5-(6H)indanedione,as an oil. 68 Mg. of the crude oxidation product,3aα,4,7,7a-tetrahydro-7aβ-methyl-1,5-(6H)indanedione was subjected tovapor phase chromatography in 14 mg. aliquots on a Barber-Coleman Model5072 equipped with flame detection at a split ration of 5:95.Fractionation gave pure3aα,4,7,7a-tetrahydro-7aβ-methyl-1,5-(6H)-indanedione, as an oil;γ_(max) 1740 and 1712 cm⁻ ¹ in the infrared spectrum. A sample wascrystallized from ether-petroleum ether, m.p. 52°-53°C.

EXAMPLE 3

45 Ml. of dimethylsulfoxide distilled from calcium hydride was added toa 53 percent dispersion of 1.03 g. of sodium hydride in mineral oilwhich had been previously washed with anhydrous ether and dried under anitrogen atmosphere. The mixture was stirred at 20°C, and a solution of5.0 grams of1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-indane in 45 ml.of dimethylsulfoxide was added at once. The reaction mixture wasagitated until hydrogen evolution ceased, approximately 4 hoursthereafter. The dimethylsulfoxide was then distilled off under highvacuo utilizing a bath kept at a temperature of 75°C. The residue(conjugate anion of1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-indane) wasdissolved in 90 ml. of anhydrous ether and added as rapidly as possible(approximately 2 minutes) to a 1 liter flask containing a thick slurryof anhydrous solid carbon dioxide in 225 ml. of anhydrous ether. Thereaction mixture was stirred vigorously. The slurry was formed bycooling 2-3 ml. of anhydrous ether with a dry ice-methanol coolingmixture and then permitting anhydrous solid carbon dioxide from aninverted tank of "bone dry" carbon dioxide to enter. The tank wasconnected to the flask with rubber pressure tubing. Two outlets wereconnected to two drying towers filled with anhydrous calcium sulfate. Asthe slurry formed and thickened, dry ether was added gradually from anaddition funnel until a total of 225 ml. had been added. The reactionmixture was stirred for 6 hours in a dry ice-methanol cooling bath andallowed to stand at 20°C for 16 hours. 200 Ml. of water containing 50ml. of 0.1 N sodium hydroxide was added to the ether solution and it wasagitated under a nitrogen atmosphere for 1 hour. The ether and waterlayers were separated and the ether layer was washed twice with water.The combined aqueous fractions were extracted with ether. The combinedether extracts were dried over sodium sulfate and evaporated in vacuoyielding starting material1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-indane. Theaqueous solution was filtered and carefully acidified with 2 Nhydrochloric acid to a pH of 2.5 at approximately 0°C. The mixture wasextracted twice with benzene and then with ether, washed with asaturated sodium chloride solution, dried over sodium sulfate, filteredand evaporated in vacuo to yield a dry solid the β-keto acid,1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-4-indane-carbocyclicacid, m.p. 153-160°C. Trituration with ether yielded1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-4-indanecarbocyclicacid, m.p. 156°C. An analytically pure sample of1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-4-indanecarbocyclicacid was obtained by recrystallization from acetone, m.p. 159.5°C.Analysis calculated for C₁₅ H₂₂ O₄ : C, 67.64; H, 8.33. Found: C, 67.63;H, 8.62.

EXAMPLE 4

1.84 Grams of unsaturated β-keto-acid1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-4-indane-carbocyclicacid was dissolved in 92 ml. of absolute ethyl alcohol and hydrogenatedin the presence of 184 mg. of 10 percent by weight palladium on bariumsulfate catalyst at atmospheric temperature and room temperature. Thetheoretical amount of hydrogen was consummed in 20 minutes. The solutionwas filtered and evaporated in vacuo, affording1β-tertiarybutoxy-3aα-4β-5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4-indane-carboxylicacid, m.p. 107.5-109°C. An analytically pure sample of1β-tertiarybutoxy-3aα-4β-5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4-indane-carbocyclicacid was obtained by recrystallization from ether, m.p. 114°-114.5°C.Analysis calculated for C₁₅ H₂₄ O₄ : C, 67.13; H, 9.02. Found: C, 66.95;H, 9.09.

EXAMPLE 5

30.7 Mg. of the β-keto acid1β-tertiary-butoxy-3aα-4β-5,6,7,7a-hexadro-7aβ-methyl-5-oxo-4-indane-carbocyclicacid was dissolved in 2.5 ml. of tetrahydrofuran to which 2.5 ml. of 2 Nhydrochloric acid was added. The reaction mixture was refluxed under anitrogen atmosphere for approximately 6 hours. It was then neutralizedwith 2 N sodium hydroxide and evaporated in vacuo. The residue wasextracted with ether and the extract was washed with a small amount ofsaturated sodium chloride solution, dried over sodium sulfate andevaporated in vacuo to give bicyclic keto alcohol3aα-4,7,7a-tetrahydro-1β-hydroxy-7aβ-methyl-5(6H)indanone as a waxysolid, m.p. 41°-42°. NMR spectra superimposable to that of3aα-4,7,7a-tetrahydro-1β-hydroxy-7aβ-methyl-5(6H)indanone, as preparedin Example 1. Analysis calculated for C₁₀ H₁₀ O₂ : C, 71.39; H, 9.59.Found: C, 71.11 H, 9.32.

EXAMPLE 5a

246 Mg. of(±)-1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7a.beta.-methyl-5-oxo-4α-indanecarboxylicacid was suspended in 6 ml. of concentrated hydrochloric acid andstirred under a nitrogen atmosphere for 2.5 hours at room temperatureuntil the compound had thoroughly dissolved. The flask was sealed undera nitrogen atmosphere and permitted to stand for approximately 20 hours.The solution was then evaporated in vacuo at 30°C. to give a mixturethat crystallized to yield a tacky crystalline-type solid upon treatmentwith acetone. The solid was ground up in 1 ml. of ether and thesupernatant decanted to give a crude product, melting point 102°-104°C.(dec.). Recrystallization from ether gave pure (±)-3aα,4β,5,6,7,7a-hexahydro-1β-hydroxy-7aβ -methyl-5-oxo-4α-indanecarboxylicacid, melting point 123°C. (dec.).

EXAMPLE 6

2.95 G. of1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4αindane-carbocyclicacid was dissolved in a mixture of 22 ml. of dimethylsulfoxide and 12.2ml. of 36-38 percent aqueous formaldehyde solution. 1.35 G. ofpiperidine hydrochloride was added and it was stirred under nitrogen for3 hours. 9.35 Mg. of sodium bicarbonate in water (100 ml.) was added tothe above reaction mixture. It was then extracted three times withbenzene. The extract was washed with water and with a saturated sodiumchloride solution, dried over magnesium sulfate, filtered and thenevaporated in vacuo to give a crude1β-tertiarybutoxy-3aα-6,7,7a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-one,as an oil. The crude methylene ketone1β-tertiarybutoxy-3aα-6,7,7a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-onewas purified by preparative thin layer chromatography on silica gel witha fluorescent indicator. The sample was applied at the rate of 30 mg.per plate which measured 8 × 8 inch × 1 mm. thick. The development wascarried out with a mixture of 92.5 percent benzene and 7.5 percent ethylacetate. The area corresponding to the major component was mechanicallyremoved from the plate and the adsorbent was suspended in ethyl acetate.Filtration through Celite was followed by evaporation in vacuo to affordpure1β-tertiarybutoxy-3aα-6,7,7a-tetrahydro-7aβ-methyl-4-methylene-indan-5(4H)-one,as an oil which crystallized upon standing in a container filled withdry-ice, m.p. 42.5°-44°C. Analysis calculated for C₁₅ H₂₄ O₂ : C, 76.22;H, 10.24 Found: C, 75.32; H, 10.25.

EXAMPLE 7

410 Mg. of freshly distilled ethyl propionyl acetate was added to 115.2mg. of the crude methylene ketone 1β-tertiarybutoxy3aα,6,7,7a-tetrahydro-7aβ-methyl-4-methyleneindan-5(4H)-one. Thereaction mixture was cooled to 0°C and 0.87 ml. of 0.1 N sodiummethoxide in methanol was added while agitating under a nitrogenatmosphere. The reaction mixture was allowed to stand for approximately18 hours at 0°C and for an additional 4 hours at 20°C. The mixture wascooled by employing an ice bath and neutralizing with 0.87 ml. of 0.1 Nhydrochloric acid. The solvent was then removed in vacuo and the residuewas extracted with methylene chloride. The extract was sequentiallywashed with water and with a saturated sodium chloride solution, driedwith sodium sulfate, filtered and evaporated in vacuo to yield crudediketoester2-(1β-tertiarybutoxy-3aα-4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4-indanylmethyl)-3-oxovaleric acid ethyl ester.

220 Mg. of the β-diketoester2(1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4-indanylmethyl)-3-oxovalericacid ethyl ester was dissolved in 4 ml. of methanol to which 4 ml. of 2N hydrochloric acid was added. The reaction mixture was stirred andrefluxed under a nitrogen atmosphere for approximately 6 hours. Thereaction mixture was then cooled by use of an ice bath and neutralizedsequentially with 0.4 ml. of 19.5 N sodium hydroxide solution and thenwith 0.4 ml. of 1.0 N sodium hydroxide solution. The solvent wasevaporated in vacuo and the residue was extracted two times with ethylacetate and once with ether. The combined extract was washed once withwater and then two times with a saturated sodium chloride solution. Thecombined extract was then dried over sodium sulfate, filtered andevaporated in vacuo to give crude2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-3β-hydroxy-3aβ-6-dimethyl-1H-benz[e]indan-7-one,an oil that could be crystallized by seeding with an authentic sample.109 Mg. of the crude BCD-tricyclic compound2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-3β-hydroxy-3aβ,6-dimethyl-1H-benz[e]indan-7-onewas purified by preparative thin layer chromatography on silica gel withfluorescent indicator. Filtration through Celite followed by evaporationin vacuo gave an oil which crystallized upon seeing with an autheticsample; trituration with a 2:1 mixture of ether gave pure2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-3β-hydroxy-3aβ,6-dimethyl-1H-benz[e]indan-7-one, m.p.131-133°C.

EXAMPLE 8

134 Mg. of the unsaturated β-keto acid,1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-4-indanecarboxylic acid was suspended in 5 ml. of ether. The suspension wascooled to 0°C and 7.6 ml. of a solution of diazomethane in ether (0.076mmoles/m) was added dropwise while stirring. After approximately 10minutes of stirring, the solution was then evaporated in vacuo to yieldthe methyl ester,1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-4-indanecarboxylic acid methyl ester, m.p. 73°-76°C. Recrystallization frompetroleum ether (boiling point 30°-60°C) gave analytically pure1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-4-indanecarboxylic acid methyl ester, m.p. 76.5°-77°C. Analysis calculated forC₁₆ H₂₄ O₄ : C, 68.54; H. 8.63 Found C, 68.41; H, 8.92.

EXAMPLE 9

50 Mg. of the acid,1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4-indanecarboxylic acid was dissolved in 1.0 ml. of ether. The solution wascooled to 0°C and 1.05 ml. of a solution of diazomethane in ether (0.19mmoles ml.) was added dropwise while stirring. After 15 minutes ofstirring, the solution was evaporated to dryness to give the β-ketoester1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4α-indanecarboxylic acid methyl ester, m.p. 112.5°-113.5°C. Recrystallizationfrom petroleum ether (boiling point 30°-60°C.) gave analytically pure1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4α-indanecarboxylic acid methyl ester, m.p. 113.0°-113.5°C. Analysis calculatedfor C₁₆ H₂₆ O₄ C, 68.05; H, 9.28. Found C, 68.09; H, 9.49.

EXAMPLE 10

54.4 Mg. of the unsaturated β-keto ester,1β-tertiarybutoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-oxo-4-indanecarboxylic acid methyl ester, was dissolved in 2.7 ml. absolute ethylalcohol and hydrogenated in the presence of 18.2 mg. of 10 percentpalladium on barium sulfate catalyst at atmospheric pressure and roomtemperature. Hydrogen uptake ceased after 15 minutes. The solution wasfiltered and evaporated in vacuo to give crude 1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4α-indane carboxylic acid methylester.

EXAMPLE 11

41 Mg. of the β-keto ester, 1β-tertiarybutoxy-3aα,5β5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4α-indane carboxylic acid methyl ester wasdissolved in a mixture of 1.25 ml. of methanol and 0.55 ml. of trimethylorthoformate. The solution was cooled with an ice bath at 0°C and 0.26ml. of 2N methyl sulfuric acid was added while stirring under nitrogen.After 5 minutes at 0°C, the mixture was allowed to stand at 20°C for 16hours. It was cooled with an ice bath and neutralized with 1 N sodiummethoxide and methanol. The solvent was evaporated in vacuo and theresidue was extracted with ether. The extract was washed with aqueoussodium bicarbonate and with a saturated sodium chloride solution, driedover sodium sulfate, filtered and evaporated in vacuo to give1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-5,5-dimethoxy-7aβ-methyl-4α-indancarboxylicmethyl ester, an oil; γ_(max) 1728.sup.⁻ 1 in the infrared spectrum.

EXAMPLE 12

160 Mg. of the ketal ester, 1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-5,5-dimethoxy-7aβ-methyl-4α-indancarboxylic methyl ester wasdissolved in 3.5 ml. of dry toluene. The solution was cooled to 0°C and4.5 ml. of a 20 percent solution of diisobutyl aluminum hydride intoluene was added over a 5 minute period while stirring under nitrogen.After an additional 30 minutes at 0°C, the mixture was allowed to standat 20°C for 16 hours. It was then cooled with an ice bath and 3.0 ml. ofmethanol was added carefully while stirring. After 10 minutes at 0°C, itwas stirred at 20°C for 1 hour. The crystalline precipitate was filteredthrough a pad of "Celite" and it was washed and extracted thoroughlywith ethyl acetate. The filtrate was washed with a saturated sodiumchloride solution, dried over sodium sulfate, filtered and evaporated invacuo to give 1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-5,5-dimethoxy-7aβ-methyl-4α-indanmethanol, andoil; γ_(max) 3575 cm⁻ ¹ in the infrared spectrum.

EXAMPLE 13

31.6 Mg. of the ketal alcohol, 1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-5,5-dimethoxy-7aβ-methyl-4α-indanmethanol wasdissolved in 1.8 ml. of acetone. The solution was cooled to 5°C and 0.2ml. of distilled water and 0.03 ml. of 2 N hydrochloric acid was addedwhile starting. After 20 minutes, the reaction mixture was neutralizedwith 0.65 ml. of a saturated sodium bicarbonate solution. The acetonewas evaporated in vacuo and the residue was extracted with ether. Theextract was washed with a saturated sodium chloride solution, dried oversodium sulfate, filtered and evaporated in vacuo to give1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4α-indanmethanol,an oil; γ_(max) 3580 and 1695 cm.sup.⁻¹ in the infrared spectrum.

EXAMPLE 14

17.4 Mg. of the β-keto alcohol,1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4α-indanmethanolwas dissolved in 0.25 ml. of dry pyridine and cooled to 0° C. 8.0 Mg. ofmethane sulfonyl chloride was added while stirring to 0.56 ml. of drypyridine. The reaction mixture was then allowed to stand at 20° C for1.5 hours. It was evaporated to dryness in vacuo and the residue wasdissolved in chloroform. The solution was then washed with water and asaturated sodium chloride solution, dried over sodium sulfate, filteredand evaporated in vacuo to give1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4α-indanmethanolmethanesulfonate, as an oil; γ_(max) 1705, 1353 and 1175 cm.sup.⁻¹ inthe infrared spectrum.

EXAMPLE 15

22.9 Mg. of the β-keto mesylate,1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4α-indanmethanolmethanesulfonate was dissolved in a mixture of 0.3 ml. of methanol and0.3 ml. of anhydrous benzene. 59.5 Mg. of ethyl propionyl acetate and0.7 ml. of 1.0 N sodium methoxide was added and the reaction mixture wasstirred at 0° C under nitrogen for 2 hours and at 20° C for 16 hours.The reaction mixture was neutralized with 0.1 N hydrochloric acid andevaporated to dryness in vacuo. The mixture was then treated twice withtoluene and taken to dryness under high vacuo to yield the diketo ester,2-(1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4-indanylmethyl)-3-oxo-valericacid ethyl ester, as an oil.

EXAMPLE 16

23.8 Mg. of the crude diketo ester,2-(1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4α-indanylmethyl)-3-oxo-valericacid ethyl ester was dissolved in 0.5 ml. of tetrahydrofuran, and 0.5ml. of 0.2 N sodium hydroxide was added while stirring at 20° C. undernitrogen. The reaction mixture was allowed to stand at room temperaturefor 16 hours. The solvent was then evaporated in vacuo, the residue wasdissolved in water and extracted with chloroform to remove neutralmaterial. The water solution was carefully acidified with 2 Nhydrochloric acid and extracted with chloroform. The extract was washedwith saturated sodium chloride solution, dried over sodium sulfate andevaporated in vacuo to give the crude β-keto acid,3β-tertiarybutoxy-2,3,3a,4,5,7,8,9,9aβ-decahydro-3aβ,6-dimethyl-7-oxo-1H-benz[e]inden-8α-carboxylic acid.3β-tertiarybutoxy-2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-3a.beta.,6-dimethyl-1H-benz[e]inden-7-onewas obtained from the above produced product by refluxing in toluene for1 hour under a nitrogen atmosphere.

EXAMPLE 17

348 Mg. of the lithium salt of the ketal acid,4-(2-methyl-1,3-dioxolan-2-yl)butanoic acid was dissolved in 5 ml.anhydrous tetrahydrofuran. The solution was cooled to 0° C and 1.25 ml.of a 1.6 molar solution of methyllithium in diethylether was addeddropwise over a period of one hour while stirring under a nitrogenatmosphere. The solution was allowed to rise approximately to 20° C andkept at this temperature over a period of 2 hours. The reaction mixturewas added to crushed ice and the organic solvents were removed in vacuo.The residue was extracted with ether, the extract was washed with asaturated sodium chloride solution, dried with magnesium sulfate,filtered and evaporated in vacuo to give crude5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone.

EXAMPLE 18

378 Ml. of dimethylsulfoxide which was distilled from calcium hydridewas added to a 53 percent dispersion of sodium hydride (29.2 g.) inmineral oil which had been washed with anhydrous hexane and dried undernitrogen. The mixture was stirred under nitrogen and heated slowly to68°-71° C. After 1.5 hours, the evolution of hydrogen ceased and aturbid grey solution of the sodium salt of the metal sulfinyl carbanionhad formed. The solution was cooled to 18° C and 60.6 g. of the ketalester 4-(2-methyl-1,3-dioxolan-2-yl)-butanoic acid ethyl ester was addedover a 40 minute period to the stirred solution at a rate such as tomaintain the exothermic reaction temperature at 18°-20° C for 1 hour.The solution was poured on ice, neutralized with cold 1 N hydrochloricacid and extracted with chloroform. The extract was washed with asaturated sodium chloride solution, dried over magnesium sulfate,filtered and evaporated in vacuo to give an oil. Volatile impuritieswere then removed under high vacuo, bath temperature maintained at 80° Cto give the β-keto sulfoxide,1-methyl-sulfinyl-5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone. Analysiscalculated for C₁₀ H₁₈ O₄ S: C, 51.26; H, 7.74; S, 13.68. Found: C,50.96; H, 7.55; S, 13.81.

EXAMPLE 19

46.2 Grams of aluminum foil was cut into approximately 3 qt. inch squarepieces and placed into a 5 lit. three necked flask, fitted with anitrogen inlet and held on a shaker in a fume hood. The aluminumcuttings were shaken with a solution of 2 lit. of 1 N aqueous sodiumhydroxide for 1-2 minutes, and the alkali was siphoned; the metal waswashed two times with 2 lit. of water in an analogous manner. The metalwas then amalgamated by shaking for 15 seconds with 2 lit. of a 2percent mercuric chloride solution in water. The mercuric chloridesolution was then siphoned off and the amalgam was washed twice with 1lit. of ethyl alcohol and once with ether. All operations were conductedunder a nitrogen atmosphere. 40.0 G. of the β-keto sulfoxide,1-methyl-sulfinyl-5-(2-methyl-1,3-dioxolan-2-yl)-2-heptanone wasdissolved in a mixture of 2160 ml. of tetrahydrofuran, 240 ml. of waterand 4 ml. of 1 N sodium hydroxide. The solution was added at once to the1 aluminum amalgam and was shaken under a rapid stream of nitrogen for 2hours to entrain the methyl mercaptan formed. The reaction mixture wasfiltered through a pad of Celite on a sintered glass funnel, and thegelatinous precipitate was washed thoroughly with ether. The mixture wasconcentrated in vacuo to a volume comprising 50 ml. and extracted withether. The extract was washed with a sodium chloride solution, driedover sodium sulfate, charcoaled with Norit A, filtered and evaporated invacuo to yield the cetal ketone,5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone. Analysis calculated for C₉H₁₆ O₃ : C, 62.76; H, 9.36. Found: C, 63.09; H, 9.42.

EXAMPLE 20

11.8 Grams (0.1 moles) of diethyl carbonate in 12.5 ml. of anhydrousether was added to 4.55 g. (0.1 moles) of a 53 percent dispersion ofsodium hydride in mineral oil which was washed with anhydrous hexane anddried under nitrogen. This mixture was stirred under nitrogen and 8.6 g.(0.05 mole) of the ketal ketone,5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone was added dropwise over aperiod of 2 hours. A gentle reflux was maintained throughout theaddition and the refluxing was continued for an additional period ofapproximately 11/2 hours. The solution was then cooled with an ice bath,20 ml. of anhydrous ether and 2 ml. of absolute ethyl alcohol was addedand it was stirred for 45 minutes to destroy any unreacted sodiumhydride. The suspension was diluted with an equal volume of ether andthe ice cold suspension was then added to a rapidly agitated mixture of6 ml. of glacial acetic acid and 200 ml. of ice water. The etheral layerwas separated, and the aqueous layer was additionally extracted twicewith ether. The extract was washed with saturated sodium bicarbonate andwith a saturated sodium chloride, dried with sodium sulfate, filteredand evaporated in vacuo to give the crude β-keto ester,6-(2-methyl-1,3-dioxolan-2-yl)-3-oxo-hexanoic acid ethyl ester, b.p.110°-112° C at 0.2 mm., Analysis calculated for C₁₂ H₂₀ O₅ : C, 59.00;H, 8.25. Found: C, 58.92; H, 8.38.

EXAMPLE 21

A mixture of 2.36 g. (0.01 moles) of freshly prepared crude methyleneketone,1β-tertiarybutoxy-3aα,6,7,7a-tetrahydro-7aβ-methyl-4-methyleneindan-5(4H)-oneand 2.68 g. (0.11 moles) of β-keto ester6-(2-methyl-1,3-dioxolan-2-yl)-3-oxo-hexanoic acid ethyl ester wascooled in an ice bath. 20 Ml. of an 0.1 normal sodium methoxide solutionin methanol was added to the above reaction mixture and the solution wasallowed to stand at 0° C for approximately 64 hours and at 20° C forabout 4 hours. The pH of the solution was then adjusted to 7.5 by meansof 0.5 N hydrochloric acid and the methanol was evaporated in vacuo. Theoily residue was dissolved in 77.5 ml. of tetrahydrofuran to which 77.5ml. of 0.2 N aqueous sodium hydroxide was added. The reaction mixturewas stirred at 20° C under a nitrogen atmosphere for 6 hours. Thetetrahydrofuran was evaporated in vacuo and the basic solution extractedwith ether. The ether extract was then washed with water and a saturatedsodium chloride solution, dried with sodium sulfate, filtered andevaporated in vacuo to give a neutral impurity. 42.5 Ml. of an aliquotof the aqueous basic solution was carefully acidified at 0° C with 5.1ml. of 0.5 N hydrochloric acid so as to attain a pH of 3.5. The reactionmixture was then immediately extracted with ethyl acetate and withether. The combined extract was washed with saturated sodium chloridesolution, dried over sodium sulfate, filtered and evaporated in vacuo togive the crude unsaturated β-keto acid,3β-tertiarybutoxy-2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-6-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3aβ-methyl-7-oxo-1H-benz[e]inden-8.alpha.-carboxylicacid, an amorphous solid. A few drops of ether were added to the crudesolid3β-tertiarybutoxy-2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-6-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3aβ-methyl-7-oxo-1H-benz[e]inden-8.alpha.-carboxylicacid and it was kept at -10° C for 72 hours. A large crystalline cropwas formed, which could be purified by trituration at room temperaturewith petroleum ether (b.p. 30°-60° C). Recrystallization from ether gaveanalytically pure3β-tertiary-butoxy-2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-6-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3aβ-methyl-7-oxo-1H-benz[e]inden-8α-carboxylicacid, m.p. 129° C. Analysis calculated for C₂₅ H₃₈ O₆ : C, 69.09, H,8.81. Found: C, 68.84; H, 8.70.

EXAMPLE 22

Crude unsaturated β-keto acid,3β-tertiarybutoxy-2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-6-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3aβ-methyl-7-oxo-1H-benz[e]inden-8.alpha.-carboxylicacid was dissolved in 50 ml. of toluene. The solution was stirred andrefluxed under nitrogen for 30 minutes. It was then cooled to roomtemperature and extracted with 0.5 N sodium bicarbonate solution andthen with a saturated sodium chloride solution. The toluene solution wasthen dried over sodium sulfate and evaporated in vacuo to give theunsaturated keto compound3β-tertiary-butoxy-1,2,3,3a,4,5,8,9,9aβ,9bα-decahydro-6-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3aβ-methyl-7H-benz[e]inden-7-oneas an oil. Similar treatment of pure β-keto acid3β-tertiarybutoxy-2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-6-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3aβ-methyl-7-oxo-1H-benz[e]inden-8.alpha.-carboxylicacid gave analytically pure 3β-tertiarybutoxy-1,2,3,3a,4,5,8,9,9aβ,9bα-decahydro-6-[2-(2-methyl-1,3-dioxolan-2-yl)-ethyl]-3aβ-methyl-7H-benz[e]inden-7-one,m.p. 85.5°-86° C. (petroleum ether, b.p. 30°-60° C.); Analysiscalculated for C₂₄ H₃₈ O₄ : C, 73.80; H, 9.81. Found: C, 73.77; H,10.13. The compound can also exist in a dimorphic modification, m.p.103.5°-104° C.

EXAMPLE 23

414.7 Mg. of the crude unsaturated keto compound,3β-tertiarybutoxy-1,2,3,3a,4,5,8,9,9aβ-9bα-decahydro-6-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3aβ-methyl-7H-benz[e]inden-7-onewas dissolved in 20.75 ml. of absolute ethyl alcohol containing 0.5percent by volume of triethylamine. The reaction mixture washydrogenated in the presence of 145 mg. of a 5 percent palladium oncarbon catalyst at 20° C. at atmospheric pressure to give the saturatedketo compound,3β-tertiarybutoxy-1,2,3,3a,4,5,5aα,6,8,9,9aβ,9bα-dodecahydro-6α-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3aβ-methyl-7H-benz[e]inden-7-oneas an oil. Catalytic hydrogenation of a pure crystalline sample of theunsaturated keto compound, 3β-tertiarybutoxy-1,2,3,3a,4,5,8,9,9aβ,9bα-decahydro-6-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3aβ-methyl-7H-benz[e]inden-7-oneunder analogous reaction conditions to that previously described yieldsanalytically pure 3β-tertiarybutoxy-1,2,3,3a4,5,5aα,6,8,9,9aβ,9bα-dodecahydro-6α-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3a.beta.-methyl-7H-benz[e]inden-7-one,m.p. 94.5°-96.0° C (petroleum ether, b.p. 30°-60° C.). Analysiscalculated for C₂₄ H₄₀ O₄ ; C, 73.43; H, 10.27. Found: C, 73.35; H,10.52.

EXAMPLE 24

407.2 Mg. of crude3β-tertiarybutoxy-1,2,3,3a,4,5,5aα,6,8,9,9aβ,9bα-dodecahydro-6α-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3aβ-methyl-7H-benz[e]inden-7-onewas dissolved in 15 ml. of methanol. 15 Ml. of 2 N hydrochloric acidwere added to the stirred solution and it was refluxed under nitrogenfor 4 hours. The reaction mixture was neutralized with 3 N sodiumhydroxide and evaporated to a small volume in vacuo. The residue wasextracted with ethyl acetate. The extract was then washed with saturatedsodium chloride solution, dried over sodium sulfate, charcoaled withNorite A, filtered and evaporated in vacuo to give a crude amorphoussolid. Trituration with petroleum ether (b.p. 30°-60° C) and finallywith 0.3 ml. of ether gave racemic 19-nortestosterone, m.p. 106°-115° C.The non-crystalline material from the mother liquors was purified bypreparative thin layer chromatography on silica gel with a fluorescentindicator. A sample was applied to a single plate measuring 8 by 8inches by 1 mm. thick. The development was carried out with a 50 percentbenzene-ethyl acetate mixture and the solvent front was permitted totravel to the top of the plate. The areas corresponding to the productwere mechanically removed from the plate and the adsorbent was suspendedin ethyl acetate. Filtration through Celite, evaporation in vacuo,purification by trituration with petroleum ether (b.p. 30°-60° C) andether gave racemic 19-nortestosterone, m.p. 112°-113° C. When using thereverse addition technique (See page 37), racemic 19-nor-testosterone isobtained with m.p. 126°-127° C.

I claim:
 1. A compound of the formula ##SPC21##wherein R₄ is hydrogen orlower alkyl; Z is CH(OR₂); R₂ is lower alkyl, lower alkoxy-lower alkyl,phenyl lower alkyl and tetrahydropyranyl; m is an integer having thevalue of 1 or 2 and R'₃ is selected from the group consisting of loweralkyl, lower cycloalkyl, phenyl or phenyl substituted with lower alkyl,lower alkoxy, nitro, amine and halogen,its optical enantiomer and theracemate thereof.
 2. A compound as in claim 1 wherein R'₃ is loweralkyl.
 3. A compound as in claim 2 wherein R₃ is selected from the groupconsisting of methyl, ethyl or propyl; m is 1, Z is CH(OR₂) and R₂ islower alkyl.
 4. The compound of claim 3 which is1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4-indanecarboxylic acid methyl ester.
 5. A compound of the formula##SPC22##wherein R₄ is hydrogen or lower alkyl, Z is CH(OR₂); R₂ islower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl ortetrahydropyranyl; and m is an integer having the value of 1 or 2,itsoptical enantiomer and the racemate thereof.
 6. A compound as in claim 5wherein R₂ is tertiarybutyl; m is 1 and R₄ is selected from the groupconsisting of methyl and ethyl.
 7. The compound of claim 6 which is1β-tertiarybutoxy-3aα,4β,5,6,7,7a-hexahydro-7aβ-methyl-5-oxo-4-indanecarboxylic acid.